Ligand activation of
peroxisome proliferator-activated receptor (
PPAR)-beta/delta and inhibition of
cyclooxygenase-2 (COX-2) activity by nonsteroidal anti-inflammatory drugs can attenuate skin
tumorigenesis. There is also evidence that attenuation of skin
tumorigenesis by inhibition of COX-2 activity occurs through
PPARbeta/delta-independent mechanisms. The present study examined the hypothesis that combining
ligand activation of
PPARbeta/delta with inhibition of COX-2 activity will cooperatively inhibit chemically induced skin
tumor progression using both in vivo and ex vivo models. A two-stage chemical
carcinogenesis bioassay was performed in wild-type and
Pparbeta/delta-null mice. After 22 weeks, cohorts of both mouse lines were divided into four experimental groups: (1) control, (2) topical application of the
PPARbeta/delta
ligand GW0742, (3) dietary administration of the
COX-2 inhibitor nimesulide, or (4) both
GW0742 and
nimesulide.
Ligand activation of
PPARbeta/delta did not influence skin
tumor progression, while a modest decrease in skin
tumor multiplicity was observed with dietary
nimesulide. Interestingly, the combined treatment of
GW0742 and
nimesulide increased the efficacy of the decrease in
papilloma multiplicity for 6 weeks in wild-type mice, but this effect was not found at later time points and was not found in similarly treated
Pparbeta/delta-null mice. Neoplastic keratinocyte lines cultured with
GW0742 and
nimesulide also exhibited enhanced inhibition of cell proliferation coincident with increased expression of
Keratin messenger RNAs. Results from these studies support the hypothesis that combining
ligand activation of
PPARbeta/delta with inhibition of COX-2 activity can inhibit chemically induced skin
tumor progression by modulating differentiation.